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|Ref Type||Journal Article|
|Authors||Lui A, New J, Ogony J, Thomas S, Lewis-Wambi J|
|Title||Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells.|
|Date||2016 Jul 16|
|Abstract Text||mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells.In this study we utilized two AI-resistant breast cancer cell lines, MCF-7:5C and MCF-7:2A, which were clonally derived from estrogen receptor positive (ER+) MCF-7 breast cancer cells following long-term estrogen deprivation. Cell viability assay, colony formation assay, cell cycle analysis and soft agar anchorage-independent growth assay were used to determine the efficacy of everolimus in inhibiting the proliferation and tumor forming potential of MCF-7, MCF-7:5C, MCF-7:2A and MCF10A cells. Confocal microscopy and transmission electron microscopy were used to evaluate LC3-II production and autophagosome formation, while ERE-luciferase reporter, Western blot, and RT-PCR analyses were used to assess ER expression and transcriptional activity.Everolimus inhibited the proliferation of MCF-7:5C and MCF-7:2A cells with relatively equal efficiency to parental MCF-7 breast cancer cells. The inhibitory effect of everolimus was due to G1 arrest as a result of downregulation of cyclin D1 and p21. Everolimus also dramatically reduced estrogen receptor (ER) expression (mRNA and protein) and transcriptional activity in addition to the ER chaperone, heat shock protein 90 protein (HSP90). Everolimus restored 4-hydroxy-tamoxifen (4OHT) sensitivity in MCF-7:5C cells and enhanced 4OHT sensitivity in MCF-7 and MCF-7:2A cells. Notably, we found that autophagy is one method of everolimus insensitivity in MCF-7 breast cancer cell lines.This study provides additional insight into the mechanism(s) of action of everolimus that can be used to enhance the utility of mTOR inhibitors as part of combination therapy for AI-resistant breast cancer.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||estrogen-receptor positive breast cancer||not applicable||Everolimus + Tamoxifen||Preclinical - Cell culture||Actionable||In a preclinical study, the combination treatment of Afinitor (everolimus) and Nolvadex (tamoxifen) resulted in decreased colony formation by 95% in estrogen-receptor (ER) positive breast cancer cell lines while in ER positive breast cancer cell lines resistant to Nolvadex (tamoxifen), colony formation formation decreased by 76% with the addition of Afinitor (everolimus) (PMID: 27421652).||27421652|
|Unknown unknown||estrogen-receptor positive breast cancer||not applicable||Everolimus||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with Afinitor (everolimus) resulted in decreased cell proliferation, reduced anchorage-independent cell growth and a decrease in PI3K/Akt/mTOR pathway signaling in estrogen-receptor positive breast cancer cell lines resistant to aromatase inhibitors (PMID: 27421652).||27421652|